Laminin-α4 Is Upregulated in Both Human and Murine Models of Obesity

Goddi, Anna; Carmona, Alanis; Schroedl, Liesl; White, Jeremy; Piron, Matthew J.; Leon, Avelino De; Casimiro, Isabel; Hoffman, Alexandria; Porras, Maria A. Gonzalez; Brey, Eric M.; Brady, Matthew J.; Cohen, Ronald N.

doi:10.3389/fendo.2021.698621

Cited by 10 publications

(20 citation statements)

References 33 publications

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“…Whole-body LAMA4 deletion is associated with decreased fat mass in mice, while obese mice and humans with obesity exhibit increased adipose tissue levels of LAMA4 [ 11 , 12 ]. Here, we investigated whether the loss of adipocyte LAMA4 contributed to alterations in body mass or body composition.…”

Section: Resultsmentioning

confidence: 99%

“…Adipose tissue LAMA4 levels are increased in human and murine obesity [ 11 ], though the consequences of this are unclear. When provided a HFD as an obesogenic stimulus, mice with whole-body LAMA4 deletion exhibit lower fat mass and preservation of insulin sensitivity compared to control mice [ 12 ].…”

Section: Resultsmentioning

confidence: 99%

“…The metabolic health of male Lama4 −/− mice has been extensively profiled [ 4 , 11 , 12 ]. These animals gain less weight in response to a high-fat diet (HFD) and have decreases in epididymal white adipose tissue (eWAT) mass and lipogenesis, with no comparable changes in subcutaneous AT [ 12 ].…”

Section: Introductionmentioning

confidence: 99%

“…In addition to their improved insulin sensitivity, Lama4 −/− mice also have significantly higher energy expenditure, attributable to increased beiging of subcutaneous AT [ 4 ]. Most recently, adipose tissue LAMA4 levels were found to be increased in HFD-fed C57BL/6J mice and adipose tissue of people with obesity [ 11 ]. Interestingly, these LAMA4 levels did not change with weight loss.…”

Section: Introductionmentioning

confidence: 99%

“…Interestingly, these LAMA4 levels did not change with weight loss. In vitro, adipocytes cultured on LN411-coated plates demonstrated alterations in genes involved in lipolysis and β-oxidation [ 11 ].…”

Section: Introductionmentioning

confidence: 99%

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Adipocyte-Specific Laminin Alpha 4 Deletion Preserves Adipose Tissue Health despite Increasing Adiposity

et al. 2022

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Laminins are heterotrimeric glycoproteins with structural and functional roles in basement membranes. The predominant laminin alpha chain found in adipocyte basement membranes is laminin α4 (LAMA4). Global LAMA4 deletion in mice leads to reduced adiposity and increased energy expenditure, but also results in vascular defects that complicate the interpretation of metabolic data. Here, we describe the generation and initial phenotypic analysis of an adipocyte-specific LAMA4 knockout mouse (Lama4AKO). We first performed an in-silico analysis to determine the degree to which laminin α4 was expressed in human and murine adipocytes. Next, male Lama4AKO and control mice were fed chow or high-fat diets and glucose tolerance was assessed along with serum insulin and leptin levels. Adipocyte area was measured in both epididymal and inguinal white adipose tissue (eWAT and iWAT, respectively), and eWAT was used for RNA-sequencing. We found that laminin α4 was highly expressed in human and murine adipocytes. Further, chow-fed Lama4AKO mice are like control mice in terms of body weight, body composition, and glucose tolerance, although they have larger eWAT adipocytes and lower insulin levels. High-fat-fed Lama4AKO mice are fatter and more glucose tolerant when compared to control mice. Transcriptionally, the eWAT of high-fat fed Lama4AKO mice resembles that of chow-fed control mice. We conclude from these findings that adipocyte-specific LAMA4 deletion is protective in an obesogenic environment, even though overall adiposity is increased.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Adipocyte-Specific Laminin Alpha 4 Deletion Preserves Adipose Tissue Health despite Increasing Adiposity

et al. 2022

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Novel prognostication biomarker adipophilin reveals a metabolic shift in uveal melanoma and new therapeutic opportunities

Matareed

Maranou

Koskela

et al. 2023

The Journal of Pathology

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Metastatic uveal melanoma remains incurable at present. We previously demonstrated that loss of BAP1 gene expression in tumour cells triggers molecular mechanisms of immunosuppression in the tumour microenvironment (TME) of metastatic uveal melanoma. Adipophilin is a structural protein of lipid droplets involved in fat storage within mammalian cells, and its expression has been identified in uveal melanoma. We comprehensively evaluated adipophilin expression at the RNA (PLIN2) and protein levels of 80 patients of the GDC‐TCGA‐UM study and in a local cohort of 43 primary uveal melanoma samples respectively. PLIN2 expression is a survival prognosticator biomarker in uveal melanoma. Loss of adipophilin expression is significantly associated with monosomy 3 status and nuclear BAP1 losses in uveal melanoma tumours. Integrative transcriptomic and secretome studies show a relationship between transient loss of adipophilin expression and increased levels of tumour‐associated macrophages and hypoxia genes, suggesting PLIN2‐dependent changes in oxygen and lipid metabolism in the TME of low and high‐metastatic risk uveal melanoma. We designed four adipophilin‐based multigene signatures for uveal melanoma prognostication using a transcriptomic and secretome survival‐functional network approach. Adipophilin‐based multigene signatures were validated in BAP1‐positive and BAP1‐negative uveal melanoma cell lines using a next‐generation RNA sequencing approach. We identified existing small molecules, mostly adrenergic, retinoid, and glucocorticoid receptor agonists, MEK, and RAF inhibitors, with the potential to reverse this multigene signature expression in uveal melanoma. Some of these molecules were able to impact tumour cell viability, and carvedilol, an adrenergic receptor antagonist, restored PLIN2 levels, mimicking the expression of normoxia/lipid storage signatures and reversing the expression of hypoxia/lipolysis signatures in co‐cultures of uveal melanoma cells with human macrophages. These findings open up a new research line for understanding the lipid metabolic regulation of immune responses, with implications for therapeutic innovation in uveal melanoma. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

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Obesity‐induced tissue alterations resist weight loss: A mechanistic review

Della Guardia,

Shin

2024

Diabetes Obesity Metabolism

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Interventions aimed at weight control often have limited effectiveness in combating obesity. This review explores how obesity‐induced dysfunction in white (WAT) and brown adipose tissue (BAT), skeletal muscle, and the brain blunt weight loss, leading to retention of stored fat. In obesity, increased adrenergic stimulation and inflammation downregulate β‐adrenoreceptors and impair catecholaminergic signalling in adipocytes. This disrupts adrenergic‐mediated lipolysis, diminishing lipid oxidation in both white and brown adipocytes, lowering thermogenesis and blunting fat loss. Emerging evidence suggests that WAT fibrosis is associated with worse weight loss outcomes; indeed, limiting collagen and laminin‐α4 deposition mitigates WAT accumulation, enhances browning, and protects against high‐fat‐diet‐induced obesity. Obesity compromises mitochondrial oxidative capacity and lipid oxidation in skeletal muscle, impairing its ability to switch between glucose and lipid metabolism in response to varying nutrient levels and exercise. This dysfunctional phenotype in muscle is exacerbated in the presence of obesity‐associated sarcopenia. Additionally, obesity suppresses sarcolipin‐induced sarcoplasmic reticulum calcium ATPase (SERCA) activation, resulting in reduced oxidative capacity, diminished energy expenditure, and increased adiposity. In the hypothalamus, obesity and overnutrition impair insulin and leptin signalling. This blunts central satiety signals, favouring a shift in energy balance toward energy conservation and body fat retention. Moreover, both obese animals and humans demonstrate impaired dopaminergic signalling and diminished responses to nutrient intake in the striatum, which tend to persist after weight loss. This may result in enduring inclinations toward overeating and a sedentary lifestyle. Collectively, the tissue adaptations described pose significant challenges to effectively achieving and sustaining weight loss in obesity.

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Laminin-α4 Is Upregulated in Both Human and Murine Models of Obesity

Cited by 10 publications

References 33 publications

Adipocyte-Specific Laminin Alpha 4 Deletion Preserves Adipose Tissue Health despite Increasing Adiposity

Adipocyte-Specific Laminin Alpha 4 Deletion Preserves Adipose Tissue Health despite Increasing Adiposity

Novel prognostication biomarker adipophilin reveals a metabolic shift in uveal melanoma and new therapeutic opportunities

Obesity‐induced tissue alterations resist weight loss: A mechanistic review

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